Small interfering RNAs (siRNAs) are widely used to study gene function owing to the ease with which they silence target genes, and there is considerable interest in their potential for therapeutic applications. siRNAs have entered human clinical trials in various disease areas. However, rapid acceptance of the use of siRNAs has been accompanied by recognition of several hurdles for the technology, including a lack of specificity. Off-target activity may complicate the interpretation of phenotypic effects in gene-silencing experiments and can potentially lead to unwanted toxicities.
PCT Patent Publication Nos. WO 2008/104978, WO 2009/044392 and WO 2011/066475 to the assignees of the present invention and hereby incorporated by reference in their entirety, disclose siRNA structures.
Oligonucleotide conjugates are referred to in, inter alia, U.S. Pat. Nos. 6,783,931; 6,919,439 and 7,235,650.
U.S. Pat. No. 6,783,931 discloses nucleosides and oligonucleosides functionalized to include alkylamino functionality, and derivatives thereof, and further discloses steriods, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosided through the alkylamino group.
U.S. Pat. Nos. 6,919,439, 7,235,650 disclose linked nucleosides having at least one functionalized nucleoside that bears a substituent such as a steroid molecule, a reporter molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, a lipid soluble vitamin, an RNA cleaving complex, a metal chelator, a porphyrin, an alkylator, a pyrene, a hybrid photonuclease/intercalator, or an aryl azide photo-crosslinking agent exhibiting increased cellular uptake and other properties.
US Patent Publication No. 2010/0172844 and Dumelin, et al. (Angew. Chem. Int. Ed. 2008, 47:3196-3201) relate to portable albumin binders and drug conjugates comprising same.
There remains an unmet need in the art for new compositions and methods that minimize, alter, or eliminate off-target effects.